Phosphatase and tensin homolog (PTEN) is a tumor-suppressor reported to be involved in the progression of numerous cancer types (Li et al. 1997; Steck et al. 1997; Baker 2007). PTEN is a negative regulator of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway—loss of PTEN leads to activation of the PI3KJAKT signal cascade and leads to increased cellular growth and proliferation. PTEN has also been shown to have other functions unrelated to PI3K/AKT signaling—for instance, in the maintenance of chromosomal stability through the physical interaction with centromeres and control of DNA repair (Shen et al. 2007). PTEN has been implicated in non-cancer indications, such as stroke, wherein down-regulation of PTEN with siRNA has been shown to have a neuroprotective effect against ischemic neuronal injury in transfected neurons (Ning et al. 2004).
Localization and degradation of PTEN has been shown to involve post-translational modifications, in particular ubiquitination (Trotman et al. 2007; Wang et al. 2007; Wang et al. 2008). PTEN localizes primarily to the cytoplasm, but a distinct pool of PTEN is known to localize to the nucleus (reviewed in (Lian and Di Cristofano 2005)). While PTEN does not contain a canonical nuclear localization signal, it does contain two PEST domains which are frequently found in proteins targeted for degradation by ubiquitination. In fact, polyubiquitination has been shown to target PTEN primarily for cellular degradation (Wang et al. 2007), while monoubiquitination is primarily involved in PTEN nuclear translocation (Trotman et al. 2007). Two specific ubiquitination sites in the PTEN protein sequence, K13 and K289, have been shown to be directly involved in PTEN nuclear translocation—monoubiquitination of either of these sites was shown to be sufficient for nuclear translocation. Mutation of either of these two sites significantly inhibited the nuclear translocation of PTEN (Trotman et al. 2007).
It is unclear whether nuclear translocation occurs in the central nervous system, and if it does, whether mechanisms for such nuclear translocation of PTEN would be the same as in other cells that have been tested to date.